Preparation of meta-substituted phenols



Patented Apr. 13, 1948 PREPARATION OF META-SUBSTITUTED PHENOLS Erwin Schwenk, Montclalr, N. J., and Domenick Papa, Brooklyn N. Y., aasignors to Schering Corporation, Bloomfield, N. 1., a corporation or New Jersey No Drawing. Application October 9, 1944, Serial No. 551,933

14 Claims. (chest-521) The present invention relates to the manufacture of phenols, and'more particularly of m-substituted phenols, by the reductive splitting of an alkylidene, and especially a methylene, dio group attached to a benzene radical.

The preparation of compounds of the benzene series having substituents, for example alkyl, alkoxy, alkylene carboxy, and other groups, in the m-po'sition to a hydroxyl group, or toa substituted hydroxyl group, like the methoxy, acetoxy and other functional groups, and likewise to other groups into which the phenolic hydroxy group may be readily converted, is .quite difllcult and the starting materials rather expensive. This 'is especially true or compounds of the type of ,8-(m-methoxy phenyl) propionic acid and similar compounds. The starting material for t-he'preparation of such compounds is usually ness with" the derivatives of such compounds having a substituent in the i-posltion, whereby iii-substituted phenols are obtained. The inven- 7 tion will accordingly be more fully described in m-hydroxy benzaldehyde or m-anisi'dine, vor similar compounds, all of which are comparatively costly and not readily available.

It is an object of the present invention to provide an eflicient and easilycontrolled process fore relatively expensive chemicals can be obtained in good yield from relatively cheap starting materials.

Other objects and advantages of the invention will appear from the following more detailed description thereof. b

We have found that phenols, particularly m-substituted phenols, can be readily obtained, and in high yield, from a benzene having an alkylidene, and especially a methylene, dioxide group, for example, piperonal, safrol, isosafrol, and other compounds with a methylene dioxy bridge of natural origin, and various derivatives thereof, by the use of a reaction which selectively ruptures the alkylidene dioxide ring and replaces it with phenolic hydroxyl in the m-position to the substituent, where the latter is present. While the reaction is applicable to methylene dioxy benzene itself, which may be called the parent substance, and to homologou alkylidene ner that the startingcompound loses one oxygen and the methylene group from the heterodetail in connection with such derivatives, and particularly with the more readily available methylene dioxy benzenes as starting materials. According to the invention, methylene dioxy benzenes are subjected to the reducing action of hydrogen in statu nascendi developed in alkaline solutlon'at room or elevated temperatures and activated by a skeleton catalyst, for-example, by treatment with Raney nickel-aluminum alloy in aqueous sodium hydroxide solution, which may or may not contain a water-miscible organic solvent like alcohol. We have found thatthis particular reduction reaction proceeds in such mancyclic ring, and the remainder or the molecule is stabilized in the form of ahydroxy compound which is obtained in unusually high yield. Thus, methylene dioxy benzene. the parent-substance,

yields phenol. while the derivatives or the parent I substance, or the general formula,

or not, yield m-substituted phenols oi the general formula This highly emcient and selective replacement of the methylene. dioxide group with a single hydroxy group in the m-position is quit unexpected in view oi the fact that the usual rupture of a methylene dioxy bridge gives the corresponding dihydroxy compounds, this being accompllshed by numerous known reagents. The extraordinarily high yieldof the m-compounds, in many instances as high as makes the fission by hydrogen generated by a Raney type alloy all 4 the more surprising and of outstanding commersystem. By the use of p-(m-methoxy phenyl) cial importance. ethyl bromide which is prepared as described While the term Raney alloy" is sometimes reabove. this substituted butyric acid can be readgarded as referring only to a nickel-aluminum ily obtained, as by the following reaction: alloy, and even to such an alloy of specific com- 5 000cm osition, the alloys useful in the present process may be of quite varied composition, but have in common the presence oi. a catalytically acting h cninr coociHl metal which is particularly active in the form of a skeleton catalyst, and likewise the presence of 00011 a metal which will liberate hydrogen in alkaline CH, solution, which the first metal will not ordinarily do. The term "Raney alloy as used herein accordingly includes not only nickel-aluminum alloys, but also other alloys having similar propm such as th discmsed 1 th patent t The reactions which have been outlined above Raney N 1,915,473; d w 1 ,11 employ th illustrate the application oi! this reduction method expression "Raney type alloy" herein to designate to J n P se f synth tic chemistry. Other an alloy containing the catalytic metal and the app s in et c chemistry o t e prephydrogen-generating m tal just referred 1-, 20 aration of compounds which are otherwise dini- The present invention accordingly provides an l l to P p n be r y und rstood. For efficient and economical process for the manufacp it w b P i to pr p re 2,7-di yture of m-substituted phenols and their substidroxy p na thr ne by the use of this reduction tuted hydroxy and other derivatives by the use of method v h Pshorr reaction:

readily available or synthesizable and inexpeno sive substances like piperonal and its derivatives, (L many of such phenols not being readily obtainable by known procedures. I

The reaction probably takes the following o 0 course: v 4 4 C a C a I coon coon i I ---0 Y O Ho cH,0 R no R OH OH I n m The parent compound (R=H) of this series, as already indicated, gives phenol; whereas m-cresol was obtained from piperonyl alcohol (R=CH2OH) and from piperonal (R=CHO). It 40 H C H0- is quite likely that the heterocyclic ring opens as indicated in I, and the intermediate compound 11, t e applications of our reaction will adi y is hydrogenolyzed into methyl alcohol and the 060111 to th e skilled in the art.

corresponding phenol 111. While various hy enenerating alloys may The ring rupture or the methylene dioxy bridge be used. best results have nerally been obtained by the action of Raneys alloy and aqueous alkali w nickel-aluminum and C pp r-magnesium can be applied to the preparation of numerous alloy intermediates which are suitable for the synthe- A w be vi m the f r ng, the reacsis of cyclopentano polyhydro phenanthrenes, tion of the present invention is independent of For example, p-(m-methoxy phenyl) ethyl brothe nature or the substituent R, whether or not mide is one of the important interm diat s r it undergoes simultaneous reduction, and so far quired for the construction of the l-keto-I- as r investigations Sh w. it may be practically methoxy octahydrophenanthrene. This substiny group, although f he P ctical standtuted ethyl bromide can be readily prepared from P in '11 is limited by the degree 01 v ilabili y of m-methoxy phenyl acetic acid which is made by the starting comp n s to a relatively m ll 1111mthe use of the reduction method of the present ber of group of radleels- Thus R may be y invention and is then converted to the desired el y. aldehyde. y eerbeelkyl. y.

intermediate, as follows: alkylene-carboxy, alkenylene-carboxy, carbo-al- 0 O O 4 Azal'actona Oxidation Reduction 6: C I -o C -o C I -0 Synthesis 7 Methylation -CHO -CH|COCOOH CHiCOOH o o o I Esteriflcation &

v -p ------o Reduction CHaO CH|COOH OHiO CHIOH CHiO CHzCHaBl In many experiments on the synthesis or kylene-carboxy, alkenylene halide, alkenyl, etc. estrone intermediates, 'y-(m-methoxy phenyl) and, as indicated, the substituents may be satbutyric acid is one of the intermediates which urated or unsaturated. Among the possible spehas round considerable application for the conciflc substituents may be mentioned CH1. struction of the octahydro phenanthrene ring CHiOH, CHO, 0068:. COOH, CHiCOOH,

asses-rs Example I for a period of about two hours with frequent shaking. The reaction mixture was then cooled, filtered from the nickel and the nickel washed twice with hot water. The combined filtrate and washings were acidified to Congo paper with cone. HCl and exhaustively extracted with ether. On evaporation of the ether there were obtained 5.2 g. of phenol which was identified through its aryioxy derivative.

Example II 10 g. of 3,4-methylene dioxy toluene were reduced as describedin Example I. After acidification of the reaction mixture it was extracted with chloroform which yielded 3.1 g. of metacresol identified through its aryloxy derivative. From the alkaline solution there were isolated 3.7 g. of the starting material.

Example III 10 g. of piperonyl alcohol were reduced as described in Example I. A 75% yield of metacresol was obtained.

Emmnle IV 10 g. of piperonal, when reduced as described in Example 1. ielded 60% of meta-cresol. It was unnecessary to use any solvent in this reduction since piperonal has a fair solubility in water. It is advisable when reducing piperonal to avoid excessive heat since under these ex: perimental conditions it has a tendency to undergo the Cannizzaro reaction.

Example v 83 g. of piperonylic acid were dissolved in 1200 cc. of water containing 150 g. of sodium hydroxide. The reaction mixture was heated to about 50 C. and 100 g. of Raney nickel-aluminum alloy were added in the course of 3 to 4 hours with stirring. At the end of the addition the reaction mixture was heated to, 90 with stirring forabout 3-5 hours. The hot solution was filtered from the suspended nickel and washed with water. The filtrate and washings were acidified to Congo paper with concentrated bydrochloric acid. After thorou hly chilling, the precipitated meta-hydroxy benroic acid was illtered. The product obtained melted at 201-202. An additional amount of the meta-hydroxy benzoie acid may be obtained by extraction of the illtrate with ether.

Example VI traction with butyl ether. After recrystallization from benzene the substance was obtained in a 75' yield of 80%. An additional amount of the metahydrow hydrocinnamic acid may be obtained by concentration of the recrystallization solvent.

Example VII 10 g. of 3,4-methylene dioxy phenyl acetic acid, which is obtained from the azaiactone of piperonal, were reduced as described in Example V. The isolation of the reduction product in this case is somewhat dimcult because of theextreme solubility of meta-hydroxy phenyl acetic acid in water. After acidification of the alkaline solution, complete extraction of the meta-hydroxy phenyl acetic acid is readily accomplished by a liquid extractor like ether. An alternative procedure for the isolation of the acid is to saturate the acidified solution with salt and extract with four 100 cc. portions of ether.

In place of an alloy containing the catalytic and the hydrogen-generating metals, there may be used the component metals, 1. e. in the free, unalloyed condition, except that the hydrogen non-generating metal, e. g. nickel, managanese, etc., is first prepared by converting an alloy ofsuch metal with an alkali-reactive metal into the skeleton catalyst form by treatment with alkali. Among the metals that may be used as the hydrogen generating component are aluminum, magnesium and calcium. After a Raney type alloy as hereinbefore defined has been used in our process, the separated skeleton catalyst can be used with. for example, powdered aluminum and alkali for treating a new batch of starting material.

We claim: 7

1. Process for the manufacture of phenols, which comprises subjecting a 1.2 methylene dioxy benzene toreductive splitting with a Raney type alloy and alkali solution to replace the methylene ether group with a phenolic hydroxyl group.

2. )Process for the manufacture of phenols, which comprises subjecting a Lil-methylene dioxy benzene substituted in the 4-position by a carboxylic acid group to reductive splitting with a Raney type alloy and aqueous alkali to replace the methylene ether group with a phenolic hydroxyl group in the m-position to the i-substituent.

3. Process for the manufacture of phenols which comprises subjecting a 1,2-methylene dioxy benzene substituted in the 4-position by a side.

chain containing a double bond, to reductive splitting with' a Raney type alloy and aqueous alkali to replace the methylene ether group with a phenolic hydroxyl group in the m-position to the side chain, the double bond of said side chain being reduced during the course of the reaction.

4.'Process for 'the' manufacture of phenols, which comprises subjecting 3,4-methylene dioxy phenyl acetic acid to reductive splitting with a Raney ype alloy and aqueous alkali to replac the methylene ether group with a phenolic hydroxyl group, whereby m-hydroxy phenyl acetic acid is formed.

5. Process for the manufacture of phenols which comprises subjecting a methylene dioxy benzene to reductive splitting with a Raney nickel-aluminum alloy and aqueous sodium hydroxidewith the application of heat to replace the methylene ether group with a phenolic hydroxyl group.

6. Process according to claim 5, wherein the benzene compound is p-piperonyl. acrylic acid, whereby meta-hydroxy hydrocinnamic acid is formed.

copper,

7. Process according to claim 5, wherein the t benzene compound is 3,4-methyiene dioxy phenyi acetic acid, whereby meta-hydroxy phenyl acetic acid is formed. and including the step or extracting such product from the reaction mixture with the aid or a water-immiscible organic solvent.

8. Process according to claim 5, wherein the benzene compound is 3,4-methylene dioxy phenyl acetic acid, whereby meta-hydroxy phenyl acetic acid is formed, and including the step of extracting such product from the reaction mixture with the aid or an organic solvent after saturating the acidified reaction mixture with a soluble salt.

9. In a process for the manufacture or p-(mmethoiw phenyl) ethyl bromide, the step which comprises subjecting 3,4-metlwlene dioxy phenyl acetic acid to reductive splitting with a Raney type alloy and aqueous alkali to replace the methylene ether group with a phenolic hydroxyl group in the m-position.

10. Process for the manufacture of phenols, which comprises subjecting an alkylidene dioxy benzene to reductive splitting with a Raney type alloy and alkali solution to replace the alkylidene ether group with a phenolic hydroxyl group.

11. Process for the manufacture of phenols, which comprises subjecting a suspension of an alkylidene dioxy benzene to the action of hydrogen developed in such suspension and activated by the presence or a skeleton metal hydrogenation catalyst oi the Haney type.

12. Process for the manufacture of phenols,

which comprises subjecting an alkylidene dioxy benzene in suspension in-an alkalene solution to the action of hydrogen developed, in such solution by the action or a metal and activated by the presence of a skeleton metal hydrogenation catalyst of the Raney type, said metals being alloyable with each other.

13. Process for the manufacture of phenols, which comprises subjecting an allqrlidene dioxy benzene in suspension in an alkaline solution to the action or hydrogen developed in such solution by aluminum and activated by the presence of a skeleton metal catalyst of the group consisting of nickel, copper and manganese,

14. Process for the manufacture of phenols, which comprises subjecting a, methylene dioxy benzene suspended in an alkali solution to the action oi! hydrogen developed in such solution by the action of a metal and in the presence 01' a. skeleton metal hydrogenation catalyst oi! the Raney type.

ERWIN SCHWENK. DOMENICK PAPA.

REFERENCES CITED 7 UNITED STATES PATENTS Name Date Amend June 30, 1936 Number 

